PUBLICATION
OXSR1 inhibits inflammasome activation by limiting potassium efflux during mycobacterial infection
- Authors
- Hortle, E., Tran, V.L., Wright, K., Fontaine, A.R., Pinello, N., O'Rourke, M.B., Wong, J.J., Hansbro, P.M., Britton, W.J., Oehlers, S.H.
- ID
- ZDB-PUB-220512-18
- Date
- 2022
- Source
- Life science alliance 5(9): (Journal)
- Registered Authors
- Oehlers, Stefan
- Keywords
- none
- MeSH Terms
-
- Animals
- Inflammasomes*/metabolism
- Mycobacterium*/metabolism
- NLR Family, Pyrin Domain-Containing 3 Protein/genetics
- NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
- Potassium/metabolism
- Signal Transduction
- Zebrafish
- PubMed
- 35545295 Full text @ Life Sci Alliance
Citation
Hortle, E., Tran, V.L., Wright, K., Fontaine, A.R., Pinello, N., O'Rourke, M.B., Wong, J.J., Hansbro, P.M., Britton, W.J., Oehlers, S.H. (2022) OXSR1 inhibits inflammasome activation by limiting potassium efflux during mycobacterial infection. Life science alliance. 5(9).
Abstract
Pathogenic mycobacteria inhibit inflammasome activation to establish infection. Although it is known that potassium efflux is a trigger for inflammasome activation, the interaction between mycobacterial infection, potassium efflux, and inflammasome activation has not been investigated. Here, we use Mycobacterium marinum infection of zebrafish embryos and Mycobacterium tuberculosis infection of THP-1 cells to demonstrate that pathogenic mycobacteria up-regulate the host WNK signalling pathway kinases SPAK and OXSR1 which control intracellular potassium balance. We show that genetic depletion or inhibition of OXSR1 decreases bacterial burden and intracellular potassium levels. The protective effects of OXSR1 depletion are at least partially mediated by NLRP3 inflammasome activation, caspase-mediated release of IL-1β, and downstream activation of protective TNF-α. The elucidation of this druggable pathway to potentiate inflammasome activation provides a new avenue for the development of host-directed therapies against intracellular infections.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping